The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA2. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6, 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.
It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
A recently published study (WOSCOPSxe2x80x94Packard et al, N. Engl. J. Med. 343 (2000) 1148-1155) has shown that the level of the enzyme Lp-PLA2 is an independent risk factor in coronary artery disease.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Furthermore, Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.
Patent applications WO 96/12963, WO 96/13484, WO 96/19451, WO 97/02242, WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham plc) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2. These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
A further class of compounds has now been identified which are non-acylating inhibitors of the enzyme Lp-PLA2. Thus, WO 99/24420 (SmithKline Beecham plc) discloses a class of pyrimidone compounds. International patent applications WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beecham plc, published after the priority date of the present application) disclose other classes of pyrimidone compounds. We have now found a further class of pyrimidone compounds which are distinguished by the substitution pattern at the 5 and 6 position of the pyrimidone ring and which have good activity as inhibitors of the enzyme Lp-PLA2.
Accordingly, the present invention provides a compound of formula (I): 
in which:
Ra is hydrogen, halogen, C(1-3)alkyl C(1-3)alkoxy, hydroxyC(1-3)alkyl, C(1-3)alkylthio, C(1-3)alkylsulphinyl, aminoC(1-3)alkyl, mono- or di-C(1-3)alkylaminoC(1-3)alkyl, C(1-3)alkylcarbonylaminoC(1-3)alkyl, C(1-3)alkoxyC(1-3)alkylcarbonylaminoC(1-3)alkyl, C(1-3)alkylsulphonylaminoC(1-3)alkyl, C(1-3)alkylcarboxy, or C(1-3)alkylcarboxyC(1-3)alkyl;
Rb is hydrogen, halogen, C(1-3)alkyl, or hydroxy(1-3)alkyl, with the proviso that Ra and Rb are not simultaneously each hydrogen; or
Ra and Rb together are (CH2)n where n is 3 or 4, to form, with the pyrimidine ring carbon atoms to which they are attached a fused 5-or 6-membered carbocyclic ring; or
Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C(1-4)alkyl, cyano, C(1-4)alkoxy or C(1-4)alkylthio, or mono to perfluoro-C(1-4)alkyl);
Rc is hydrogen or C(1-3)alkyl;
R2 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl (preferably C(1-6)alkyl), C(1-18)alkoxy (preferably C(1-6)alkoxy), C(1-18)alkylthio (preferably C(1-6)alkylthio), arylC(1-18)alkoxy (preferably arylC(1-6)alkoxy), hydroxy, halogen, CN, COR6, carboxy, COOR6, NR6COR7, CONR8R9, SO2NR8R9, NR6SO2R7, NR8R9, mono to perfluoro-C(1-4)alkyl, mono to perfluoro-C(1-4)alkoxyaryl, and arylC(1-4)alkyl;
R3 is hydrogen, C(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR6, COR6, carboxy, COOR6, CONR8R9, NR8R9, NR8COR9, mono- or di-(hydroxyC(1-6)alkyl)amino and N-hydroxyC(1-6)alkyl-Nxe2x80x94C(1-6)alkylamino, for instance, 1-piperidinoethyl; or
R3 is Het-C(0-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring comprising N and optionally O or S, bonded through a carbon ring atom and in which N may be substituted by COR6, COOR6, CONR8R9, or C(1-6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR6, COR6, carboxy, COOR6, CONR8R9 or NR8R9, for instance, piperidin-4-yl, pyrrolidin-3-yl;
R4 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl (preferably C(1-6)alkyl), C(1-18)alkoxy (preferably C(1-6)alkoxy), C(1-18)alkylthio (preferably C(1-6)alkylthio), arylC(1-18)alkoxy (preferably arylC(1-6)alkoxy), hydroxy, halogen, CN, COR6, carboxy, COOR6, NR6COR7, CONR8R9, SO2NR8R9, NR6SO2R7, NR8R9, mono to perfluoro-C(1-4)alkyl a perfluoro-C(1-4)alkoxy;
R5 is an aryl or heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl (preferably C(1-6)alkyl), C(1-18)alkoxy (preferably C(1-6)alkoxy), C(1-18)alkylthio (preferably C(1-6)alkylthio), arylC(1-18)alkoxy (preferably arylC(1-6)alkoxy), hydroxy, halogen, CN, COR6, carboxy, OOR6, CONR8R9, NR6COR7, SO2NR8R9, NR6SO2R7, NR8R9, mono to perfluoro-C(1-4)alkyl and mono to perfluoro-C(1-4)alkoxy;
R6 and R7 are independently hydrogen or C(1-20)alkyl, for instance C(1-4)alkyl (e.g. methyl or ethyl);
R8 and R9 which may be the same or different is each selected from hydrogen, C(1-12)alkyl (preferably C(1-6)alkyl); or
R8 and R9 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C(1-4)alkyl, C(1-4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; or
R8 and R9 which may be the same or different is each selected from CH2R10, CHR11CO2H or a salt thereof in which:
R10 is COOH or a salt thereof, COOR12, CONR6R7, CN, CH2OH or CH2OR6;
R11 is an amino acid side chain such as CH2OH from serine;
R12 is C(1-4)alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;
n is an integer from 1 to 4, preferably 1 or 3, more preferably 1;
X is O or S;
Y is (CH2)p(O)q in which p is 1, 2 or 3 and q is 0 or p is 2 or 3 and q is 1; and
Z is O or a bond.
Representative examples of Ra include chloro, bromo, methyl, ethyl, n-propyl, methoxy, hydroxymethyl, hydroxyethyl, methylthio, methylsulphinyl, aminoethyl, dimethylaminomethyl, acetylaminoethyl, 2-(methoxyacetamido)ethyl, mesylaminoethyl, ethylcarboxy, methanesulfonamidoethyl, (methoxyacetamido)ethyl and iso-propylcarboxymethyl.
Representative examples of Rb include hydrogen, and methyl.
Representative examples of Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached forming a fused benzo or heteroaryl ring ring include benzo (to give a quinazolinyl ring), pyrido and thieno, respectively.
Preferably Ra is methyl or ethyl and Rb is hydrogen or methyl, or Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached form a fused 5- or 6-membered carbocyclic ring. More preferably, Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached form a fused 5-membered carbocyclic ring.
Representative examples of Rc include hydrogen and methyl. Preferably, Rc is hydrogen.
Preferably, X is S.
Preferably, Y is CH2.
Preferably, Z is a direct bond.
Representative examples of R2 when an aryl group include phenyl and naphthyl. Representative examples of R2 when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
Preferably, R2 is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-6)alkyl, C(1-6)alkoxy, C(1-6)alkylthio, hydroxy, halogen, CN, mono to perfluoro-C(1-4)alkyl, mono to perfluoro-C(1-4)alkoxyaryl, and arylC(1-4)alkyl. More preferably, R2 is phenyl optionally substituted by halogen, preferably from 1 to three fluorine atoms, most preferably 4-fluoro.
Preferably, R2CH2X is 4-fluorobenzylthio. Representative examples of R3 include hydrogen, methyl, 2-(ethylamino)ethyl, 2-(diethylamino)ethyl, 2-(ethylamino)-2-methylpropyl, 2-(t-butylamino)ethyl, 1-piperidinoethyl, 1-ethyl-piperidin-4-yl.
Preferably, R3 is C(1-3)alkyl substituted by a substituent selected from NR8R9; or R3 is Het-C(0-2)alkyl in which Het is a 5- to 7-membered heterocyclyl ring comprising N and in which N may be substituted by C(1-6)alkyl. More preferably, R3 is 2-(diethylamino)ethyl.
Representative examples of R4 include phenyl, pyridine and pyrimidine. Preferably, R4 is phenyl.
Representative examples of R5 include phenyl or thienyl, optionally substituted by halogen or trifluoromethyl, preferably at the 4-position. Preferably, R5 is phenyl substituted by trifluoromethyl, preferably at the 4-position.
Preferably, R4 and R5 together form a 4-(phenyl)phenyl, 2-(phenyl)pyrimidinyl or a 2-(phenyl)pyridinyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position. More preferably, R4 and R5 together form a 4-(4-trifluoromethylphenyl)phenyl moiety.
It will be appreciated that within the compounds of formula (I) there is a sub-group of compounds which has the formula (IA): 
in which:
Ra, Rb, Rc, n, R2, R3, R4, R5, and X are as hereinbefore defined; and
a further sub-group of compounds which has the formula (IB): 
xe2x80x83in which:
Ra, Rb, R2, R3, R4, R5, and X are as hereinbefore defined, in particular:
Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached form a fused 5-membered carbocyclic ring;
R2CH2X is 4-fluorobenzylthio;
R3 is C(1-3)alkyl substituted by NR8R9; or
R3 is Het-C(0-2)alkyl in which Het is a 5- to 7- membered heterocyclyl ring containing N and in which N may be substituted by C(1-6)alkyl.;
R4 and R5 form a 4-(4-trifluoromethylphenyl)phenyl moiety;
R8 and R9 which may be the same or different is each selected from hydrogen, or C(1-6)alkyl); and
X is S.
Pharmaceutically acceptable in vivo hydrolysable ester groups for R12 include those which break down readily in the human body to leave the parent acid or its salt. Pharmaceutically acceptable in vivo hydrolysable ester groups are well known in the art and examples of such for use in R12 are described in WO 00/68208 (SmithKline Beecham).
It will be appreciated that when Rc is C(1-3)alkyl, the carbon to which it is attached will be a chiral centre so that diastereoisomers may be formed. In the absence of further chiral centres, these will be enantiomers. The present invention covers all such diastereosiomers and enantiomers, including mixtures thereof.
It will be appreciated that in some instances, compounds of the present invention may include a basic function such as an amino group as a substituent. Such basic functions may be used to form acid addition salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids. Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
It will be appreciated that in some instances, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as the sodium and potassium salts.
When used herein, the term xe2x80x9calkylxe2x80x9d and similar terms such as xe2x80x9calkoxyxe2x80x9d includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the term xe2x80x9carylxe2x80x9d refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl.
When used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring system may include a carbocyclic ring.
When used herein, the terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
Preferred compounds of formula (I) include:
1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-one;
1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-ethylpyrimidin-4-one;
1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one;
1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one; and
1-(N-(2-(Diethylamino)ethyl)-N-(2-(4-trifluoromethylphenyl)pyrimid-5-ylmethyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one;
or a pharmaceutically acceptable salt thereof;
in particular:
1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidinone; or a pharmaceutically acceptable salt thereof.
Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are re-crystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or re-crystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).
Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the primary and secondary prevention of acute coronary events, for instance those caused by atherosclerosis, including peripheral vascular atherosclerosis and cerebrovascular atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy.
The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid oxidation in conjunction with enzyme activity, for example, in addition to conditions such as atherosclerosis and diabetes, other conditions such as ischaemia, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer""s Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation.
Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid oxidation in conjunction with Lp-PLA2 activity; or with endothelial dysfunction.
Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lp(a). Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs. Examples of agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham).
It is expected that compounds of the present invention may be used in combination with cholesterol lowering agents, for instance co-administered with a statin. The statins are a well known class of cholesterol lowering agents (HMG-CoA reductase inhibitors) and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S4522, Astra Zeneca). The two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.
A substantial minority (approx 30%) of patients with elevated levels of cholesterol are found to not respond to treatment with a statin. In a further use, a compound of the present invention is administered to a patient who has failed to respond to treatment with a statin.
A further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser, as coronary heart disease is a major cause of death for diabetics. Within this class, preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance GI262570 (Glaxo Wellcome) and the glitazone class of compounds such as rosiglitazone (Avandia, SmithKline Beecham), troglitazone and pioglitazone.
Preferred indications include primary and secondary prevention of acute coronary events, for instance those caused by atherosclerosis, including peripheral vascular atherosclerosis and cerebrovascular atherosclerosis; adjunctive therapy in prevention of restenosis, and delaying the progression of diabetic/hypertensive renal insufficiency.
In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intra-muscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
A compound of formula (I) may be prepared by reacting a compound of formula (II): 
in which X, n, Ra, Rb and R2 are as hereinbefore defined,
with a compound of formula (III):
R5ZR4xe2x80x94YRcNHR3xe2x80x83xe2x80x83(III)
in which Rc, R3, R4, R5, Y and Z are as hereinbefore defined; under amide forming conditions.
Amide forming conditions are well known in the art, see for instance Comprehensive Organic Synthesis 6, 382-399, and include reacting the acid compound of formula (II) and the amine compound of formula (III) in an inert solvent such as dichloromethane, at ambient temperature, in the presence of a coupling agent. Preferred coupling agents include those developed for use in peptide chemistry, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (xe2x80x9cEDCxe2x80x9d), preferably in the presence of an additive such as 1-hydroxybenzotriazole, or O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (xe2x80x9cHATUxe2x80x9d), preferably in the presence of di-isopropylethylamine.
Compounds of formula (I) may also be prepared by a number of other processes, for instance:
(a) reacting a compound of formula (IV): 
in which X, Ra, Rb and R2 are as hereinbefore defined,
with a compound of formula (V):
R5Zxe2x80x94R4xe2x80x94YRcNR3xe2x80x94COxe2x80x94(CH2)nxe2x80x94L1xe2x80x83xe2x80x83(V)
in which n, R3, R4, R5, Rc, Y and Z are as hereinbefore defined, and L1 is a leaving group such as halogen, for instance bromo iodo, or triflate;
in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane;
(b) when X is S, reacting a compound of formula (VI): 
in which n, Ra, Rb, Rc, R3, R4, R5, Y and Z are as hereinbefore defined,
with a compound of formula (VII):
R2xe2x80x94CH2xe2x80x94L1xe2x80x83xe2x80x83(VII)
in which R2 and L1 are as hereinbefore defined,
in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane; or
(c) when X is O, reacting a compound of formula (VIII): 
in which n, Ra, Rb, Rc, R3, R4, R5, Y and Z are as hereinbefore defined, and L2 is a leaving group such as halogen or alkylthio, for instance methylthio,
with a compound of formula (IX):
R2xe2x80x94CH2xe2x80x94OHxe2x80x83xe2x80x83(IX)
in which R2 is as hereinbefore defined,
in the presence of a base such as 4-dimethylaminopyridine, in an inert solvent such as pyridine.
It will be appreciated that an initially prepared compound of formula (I) may be converted to another compound of formula (I), by functional group modification, using methods well known to those skilled in the art, for example converting a compound of formula (I) in which Ra is aminoalkyl to a compound of formula (I) in which Ra is alkylcarbonylaminoalkyl, by reaction
Compounds of formulae (II), (IV), (VI) and (VIII) for use in the above processes may be prepared by processes illustrated in the following scheme I: 
in which:
L3 is a C(16) alkyl group, for instance methyl;
R15 is a C(16) alkyl group, for instance ethyl or t-butyl and
L1, L2, Ra, Rb, Rc, R2, R3, R4, R5, n, X, Y and Z are as hereinbefore defined.
With reference to Scheme I:
Amide forming conditions for step (a) are well known in the art. Preferably, the acid of formula (II) is reacted with the amine of formula (III) in an inert solvent, such as dichloromethane, at ambient temperature and in the presence of a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate and di-isopropylethylamine or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole.
Alkylation conditions for step (b) include reaction in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as
Conditions for step (c) include hydrolysis, for instance using aqueous sodium hydroxide in a solvent such as dioxan or, when R15 is t-butyl, dealkylation with an acid such as trifluoroacetic acid in a solvent such as dichloromethane.
Conditions for step (d) include under thioether forming conditions. Advantageously, the reaction is carried out in the presence of a base such as sodium ethoxide or potassium carbonate, preferably in a solvent such as ethanol, dimethyl formamide or acetone, or a secondary or tertiary amine base such as di-isopropylethylamine, in solvent such as dichloromethane.
In step (e), a compound of formula (XVII) is reacted with thiourea, in the presence of sodium ethoxide (preferably generated in situ from sodium and ethanol).
In step (f), a compound of formula (XVIII) is reacted with ethyl formate in the presence of a base such as sodium hydride or potassium iso-propoxide.
In step (g), a compound of formula (IV) is reacted with a compound of formula (V) in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane
In step (h), a compound of formula (XIII) is reacted with a compound of formula (XIV) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide.
In step (i), a compound of formula (XVI) is reacted with a metal thiocyanate, for example potassium thiocyanate, in a solvent such as acetonitrile.
In step (j), a compound of formula (XVII) is reacted with a methylating agent such as dimethyl sulphate in the presence of a base such as potassium carbonate, followed by hydrolysis of the intermediate ester in conventional manner e.g. by basic hydrolysis using sodium hydroxide to give the corresponding carboxylic acid which may then be converted into the acyl chloride, for instance by treatment with oxalyl chloride.
In step (k), a catalyst such as 4-dimethylaminopyridine, and in a solvent such as pyridine are used.
In step (I), a compound of formula (XIII) is reacted with a compound of formula (XV) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide.
In step (m) a compound of formula (XX) is converted to a compound of formula (XIX), in which Ra is halogen, by treatment with N-halosuccinimide, for example N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride.
Compounds of formula (II) and (IV), in particular wherein Ra and Rb together with the pyrimidine ring carbon atoms to which they are attached form a fused 5-membered carbocyclic ring, are novel and form a further aspect of the present invention.